Efficacy and safety of LAU-7b in a Phase 2 trial in adults with cystic fibrosis.

BACKGROUND: Lung inflammation is associated with tissue damage in cystic fibrosis (CF). LAU-7b, a novel oral drug candidate, was shown to control inflammation and stabilize CFTR protein in the epithelial membrane during inflammatory stress in preclinical models of CF. METHODS: A double-blind, randomized, placebo-controlled Phase 2 study was conducted to evaluate efficacy and safety of LAU-7b in adults with CF. LAU-7b or placebo was administered over 24 weeks as six 21-day treatment cycles each separated by 7 days. The primary efficacy endpoint was the absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) at 24 weeks. RESULTS: A total of 166 subjects received at least one dose of study drug (Intent-To-Treat population, ITT), of which 122 received ≥5 treatment cycles (Per-Protocol population, PP). Both treatment arms showed a mean lung function loss at 24 weeks of 1.18 ppFEV1 points with LAU-7b and 1.95 ppFEV1 with placebo, a 0.77 ppFEV1 (40 s) difference, p=0.345, and a 0.95 ppFEV1 (49 %) difference in the same direction in PP population, p=0.263. Primary analysis of mean ppFEV1 through 24 weeks showed differences of 1.01 and 1.23 ppFEV1, in the ITT (65 % less loss, p=0.067) and PP populations (78 % less loss, reaching statistical significance p=0.049), respectively. LAU-7b had an acceptable safety profile. CONCLUSION: Although the study did not meet its primary efficacy endpoint in the ITT population, LAU-7b was generally well tolerated and showed evidence of preservation of lung function to support further development.

Lack of effect of sex and disease state on the pharmacokinetics of porfimer sodium.

BACKGROUND: Porfimer sodium is an agent used for photodynamic therapy (PDT) of cancer and other pre-malignant conditions such as high grade dysplasia in Barrett's oesophagus. Since it is activated by non-thermal red light after a 2-day time interval to allow distribution in the target tissues, its pharmacokinetic properties are relevant to the timing of light treatment and to the period of protection against photosensitivity reactions. With the recent availability of a reliable assay overcoming the limitations of previous assays, two definitive pharmacokinetic studies were undertaken. OBJECTIVE: To determine if sex or a target disease state (cancer) have an effect on porfimer sodium pharmacokinetic parameters. METHODS: Twenty-four healthy volunteers (12 men and 12 women) and five male patients with oesophageal cancer undergoing palliative PDT for their obstructive lesions were enrolled. All received an intravenous injection of porfimer sodium (Photofrin) 2 mg/kg over 3-5 minutes and underwent serial blood samplings over 35 days postdose. Porfimer sodium was quantified in serum by a validated spectrofluorometry assay and low-level pre-existing interference was subtracted from postdose concentrations. RESULTS: The two sexes had comparable maximum serum concentrations with a ratio of 0.95. Women tended to have higher areas under the serum concentration-time curve from time zero to the last sampling time, and from time zero to infinity than men, but the difference did not reach significance (ratios of means of 1.18 and 1.20, respectively). Elimination parameters also showed no sex-related differences with a mean distribution half-life of 9.5 hours, clearance of 0.88 mL/h/kg and a terminal elimination half-life of 415 hours (17.3 days). The sexes only differed significantly for the time to reach maximum serum concentration (means of 1.54 and 0.165 hours, for women and men, respectively; p = 0.0239). This is probably because of the sparse sampling schedule and the plateau behaviour of the initial concentrations. The pharmacokinetic parameters in cancer patients were generally comparable to healthy volunteers. However, the mean terminal elimination half-life was 30% shorter (283 hours or 11.8 days) in cancer patients. CONCLUSION: Sex does not have an effect on porfimer sodium pharmacokinetics. The presence of advanced oesophageal cancer does not seem to have any influence either. These findings confirm that there is no need for sex-specific label recommendations. Also, the elimination phase of porfimer sodium starting progressively from 24 hours postdose supports the recommended time interval for laser light application, the window for PDT debridement and the skin protection period of at least 30 days.

Duration of skin photosensitivity and incidence of photosensitivity reactions after administration of verteporfin.

BACKGROUND: Verteporfin (Visudyne, Novartis AG) is a light-activated drug that reduces the risk of vision loss in patients with certain types of choroidal neovascularization (CNV). Because photosensitivity can occur with photosensitizers, it is important for ophthalmologists providing verteporfin therapy to understand its time course and duration, as well as the incidence of photosensitivity reactions. METHODS: Data were obtained from three sources: 1) the time course of skin photosensitivity in 17 volunteers by measuring erythema/edema over time after verteporfin, using red light exposure; 2) the duration of skin photosensitivity in 30 patients with skin cancer by exposing skin to simulated solar light and calculating the daily minimal erythematous dose; and 3) the incidences of photosensitivity reactions as recorded in three phase III trials in patients with CNV secondary to age-related macular degeneration or pathologic myopia who received the regimen of verteporfin therapy currently approved by regulatory authorities (infusion of 6 mg/m(2) body surface area). RESULTS: 1) Skin photosensitivity was high at the first timepoint of 1.5 hours after dosing and decreased rapidly thereafter; 2) the duration of skin photosensitivity was dose dependent, ranging from 2.0 to 6.7 days at 6 to 20 mg/m(2), respectively (mean of 2 days at a dose of 6 mg/m(2)); and 3) photosensitivity reactions occurred in only 2.2% of patients in the phase III trials, including two severe events, one secondary to extravasation. All treatment-related reactions in the phase III trials occurred within the first 2 days after dosing, with the exception of two mild reactions and one moderate reaction that occurred 3 days after treatment. CONCLUSIONS: Verteporfin is associated with short-lived photosensitivity and a low incidence of photosensitivity reactions in clinical trials, most of which could probably have been avoided by adherence to protocol instructions for skin protection.

Clinical pharmacokinetics of verteporfin.

Verteporfin, a benzoporphyrin derivative, is the first photo-sensitive (light-activated) drug to be proven effective in treating certain types of choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). The pharmacokinetics of light-activated drugs are central to their safety and efficacy. Forty healthy Caucasian volunteers, 24 healthy Japanese volunteers, 9 patients with mild hepatic dysfunction, 69 patients with CNV due to AMD, and 21 patients with skin cancer were infused with verteporfin 3 to 20 mg/m2 of body surface area over 1.5 to 45 minutes. Verteporfin regioisomers and the metabolite benzoporphyrin derivative diacid (BPD-DA) were quantified by validated methods of liquid chromatography and capillary electrophoresis with laser-induced fluorescence. Cmax of verteporfin occurred at the end of the infusion and was proportional to the dose and rate of infusion. The extent of formation of the metabolite BPD-DA was less than 10%, based on the AUC ratio. Renal elimination was minimal (< 0.01% of the dose). All groups studied had similar pharmacokinetics, which were biexponential with distribution in the first 1 to 3 hours and elimination t(1/2) of 5 to 6 hours. No significant differences were observed between Japanese and Caucasian volunteers or between men and women. Patients older than 65 years had a slightly higher average Cmax than patients younger than 65 years (1.14 vs. 1.03 microg/ml, p = 0.066), but the ranges of the two age groups overlapped. Verteporfin has a short half-life and is rapidly eliminated in the bile, mainly as unchanged drug. Based on pharmacokinetic data, dose adjustments are not required for age, gender, race, or mild hepatic or renal impairment. The rapid elimination of verteporfin shows that the period of skin photosensitivity is unlikely to persist after 24 to 48 hours.